1. Field of the Invention
The present invention relates to a novel formulation for enhancing the bioavailability of curcuminoids comprising an extensive gel forming non digestible but fermentable soluble dietary polysaccharide fiber galactomannan containing proteins purified from the well known spice, fenugreek. The invention also relates to a method of making a formulation of curcuminoids. The method involves impregnation of curcuminoids in a soluble fiber matrix to produce microencapsulates which possess a unique binding and enhanced solubility and compatibility under gastrointestinal conditions to protect the curcuminoids in the upper gastrointestinal tract and facilitate its slow release in the colon for better absorption. The invention helps in overcoming the poor systematic bioavailability upon oral administration which differ significantly in its properties with regard to efficacy was demonstrated in animals and human volunteers.
2. Description of the Prior Art
Curcuminoids, (a mixture of polyphenolic phytochemicals viz., curcumin, demethoxycurcumin and bisdemethoxycurcumin, hereinafter referred to as curcumin) is obtained from the common curry spice, turmeric (Curcuma longa L). It has been scientifically researched that curcumin has effective therapeutic properties. It acts as an antioxidant, anti-inflammatory, antispasmodic, anticoagulant, anticarcinogenic, and is involved in immunomodulatory activities and heals wounds. It is hepato- and nephro protector with strong capacity to reduce proliferation of a variety of malignant and normal cells, to induce apoptosis and to suppress tumour initiation, promotion and metastasis. In Caughey et. al., (J Virol. 2003, 77(19): 10288-94) it is stated that curcumin is one of the most effective natural molecule for many dreadful ailments and age related diseases ever tested in vitro, although it did not work in vivo with oral dosing of unstated formulation.
Curcumin has shown to act mainly by down regulating the transcription factors like NF-kB which leads to decreased gene expression of cytokines (TNF-α, IL-1β, iNOS), chemokines (MCP-1), and other inflammatory proteins (COX-2) that are critical mediators in inflammatory diseases (Jurenka J S et al 2009). Curcumin's activity as anticancer, chemosensitization, and radiosensitization agent has been shown to be by down-regulating the MDM2 oncogene through the PI3K/mTOR/ETS2 Pathway (Li et al., 2007). In the case of Alzheimer's disease curcumin offers its benefit by effectively chelating with amyloid plaques forming peptides, chelating metal ions that cause lipid, protein and DNA oxidative damage and inhibiting NF-kB transcription and the production of TNF-α, under conditions of oxidative damage and inflammation (Yang et al, 2005).
The limiting factor of curcumin despite its immense therapeutic effectiveness is due to its poor absorption in the Gastrointestinal tract, which reduces its bioavailability. When taken orally, only traces of curcumin appear in the blood, whereas most of the dose is excreted through the feces. Sharma et. al. (Clin Cancer Res 2004, 10(20), 6847-54) states that most curcumin activities require 0.1-2 micromolar levels in vitro, but current supplements result only in negligible, low nanomolar blood levels. It is also stated in Garcea G et. al, (Br J Cancer, 2004, 90(5): 1011-15) that Sharma's group at Leicester has tried repeatedly and has been unable to achieve significant blood levels beyond the low nanomolar range. They also conclude that delivery of effective concentrations of oral curcumin to systematic tissues (outside the GI tract) is “probably not feasible”.
In Sharma R. A et. al., (Clin. Cancer res., 2001, 7:1834-1900) it is shown that curcumin bioavailability in humans is poor, as seen from the results of a pilot study of standardized turmeric extract in colorectal cancer patients. In Pan, M. H et. al, (Drug Metabol. Dispos., 1999, 27: 486-94) it is stated that curcumin undergoes rapid metabolic O-conjugation to curcumin glucronide and curcumin sulfate and bioreduction to tetrahydrocurcumin, hexahydrocurcumin and hexahydrocurcuminol in rats and mice in vivo. Metabolic conjugation and reduction of curcumin was more in human than in rat intestinal tissue (Ireson et. al., 2002)
Although p.o, administered curcumin has poor bioavailability and only low or non-measurable blood levels were observed (Perkins, S. et al. Cancer Epidemiol. Biomark. Prev., 2002, 11: 535-40), this route of administration inhibits chemically induced skin and liver carcinogenesis (Chiang, S. E. et al, Carcinogenesis, 2000, 21: 331-35). Oral administration of curcumin also inhibits the initiation of radiation-induced mammary and pituitary tumours (Inano, H. et al, Carcinogenesis, 2000, 21:1835-41). Similarly in a study to assess the curcumin levels in the colorectum, a daily dose of 3.6 g curcumin achieves pharmacologically effective levels in the colorectum with only negligible distribution of curcumin outside the gut, blood and liver tissues (Garcea, G. et al, Cancer Epidemiol. Biomark Prev., 2005, 14:120-25).
The factors that limit the curcumin absorption are the rapid glucuronidation/sulfation of curcumin's phenolic hydroxyl group, the instability of curcumin in aqueous solution at pH 7 and above and hydrophobicity and insolubility in water at acidic pH, when delivered as a dry powder in existing supplements. Most curcumin is never absorbed and simply passes through the GI tract and is excreted (Anand et al, 2007, 4(6), 807).
The prior art in the field is pure curcuminoids which is readily conjugated in the intestine and liver to form curcumin glucuronides and curcumin sulfates or reduced to hexahydrocurcumin. High dosage like 3 to 4 g per Kg, fails to achieve detectable plasma levels in humans and itself explains limited success rate in translating the in vitro results to the clinic.
US Patent Application 1998/5744161 describes the administration of piperine along with curcumin enhances the bioavailability of curcumin. However the level of enhancement was only modest and no curcumin could be detected after 3 hours even when supplemented with piperine. This approach has its disadvantage as most glucuronidation takes place in the upper GI tract, where the pH is acidic and curcumin is not completely dissolved until pH 8.5 and higher. In addition, the formulation acts by inhibiting the glucuronidation, which may cause serious health risks, as glucuronidation is protective against many toxins and involved in the metabolism of commonly used drugs.
Another prior art is US Patent Application US20070148263 in which the invention relates to a formulation of curcuminoid with the essential oil of turmeric to enhance the bioavailability of curcumin and to augment the biological activity of curcumin. In this formulation, Ar-turmerone, the main constituent of the essential oil was reported to be responsible for the enhanced bioavailability of curcumin. The disadvantage of this invention is that this formulation also acts by inhibiting glucuronidation.
Yet another art WO 2007103435 involves the formulation comprising curcumin, an antioxidant, a water solubilising carrier, and optionally a glucoronidation inhibitor forming a curcuminoid-lipid micelle and finally provides as an emulsion or solid-lipid nanoparticles. The method claims to have 5-times bioavailability in animals upon 100 mg/kg level supplementation, as compared to normal curcumin. Though this method claim to have more than five times bioavailability upon 100 mg/kg level supplementation, as compared to normal curcumin, the final composition contain only 2 to 3% curcumin, which may require substantial amount of consumption, even to achieve 100 mg/kg level. Moreover, the clinical safety of nanoparticles for consumption has not been finalised so far.
Another art WO 2007101551 involve phospholipid complexes of curcumin for improved bioavailability. In a study conducted on rats, peak plasma levels and area under the plasma concentration time curve (AUC) values for parent curcumin after administration of curcumin complexed with phospholipids were only five-fold higher than the equivalent values seen after treatment.
Though a minimum concentration of 0.1 μM curcumin in plasma was established for the in vitro efficacy, the oral delivery of even 3.6 g to humans could detect only nanomolar in vivo levels, after an hour of consumption (Sharma et al., 2004). Marczylo et al (2007) have reported a plasma concentration of 6.5±4.5 nM after 30 min of oral administration at 340 mg/kg on rats. Many attempts based on adjuvant, liposomes, micelles, phospholipid complexes and nanoparticles have also been reported to circumvent the problems of poor bioavailability of curcuminoids (Anand et al., 2007).